Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: water-soluble, nephrotropic, low osmolar X-ray contrast medium.
ATC code: V08AB05
The opacifying substance in Ultravist is iopromide, a non-ionic water-soluble derivative of triiodinated isophthalic acid with a molecular weight of 791.12 in which the firmly bound iodine absorbs the X-rays.

Injection of iopromide opacifies vessels or body cavities in the path of flow of the contrast agent, permitting visualisation of the internal structures until the product becomes too diluted.
Contrast-enhanced mammography (CEM)
Nine studies in a total of 1 531 patients focused on diagnostic performance in relevant fields of application.

In studies evaluating suspected breast lesions, CEM displayed a sensitivity of 96.9% to 100% and a specificity of between 69.7% and 87%, compared with digital mammography which showed a sensitivity of 96.9% and a specificity of 42.0%.

In comparative studies evaluating the precision of CEM compared with other diagnostic methods, CEM showed a difference in sensitivity and negative predictive value compared with MRI. (sensitivity 100% versus 93%; p=0.04 and NPV 100% versus 65%; p<0.001).

In addition, compared with full-field digital mammography (FFDM) combined with ultrasonography, CEM showed a sensitivity of 92.3% compared with 89.8% (p<0.05), a positive predictive value (PPV) of 93% compared with 88.7% (p<0.01) and precision of 90.2% compared with 87% (p<0.05).

In patients in whom MRI was contraindicated, there was a significant correlation between mammography and CEM classification and the histopathological classification. CEM showed a sensitivity of 98.8% and a specificity of 54.6% compared with 89.2% and 36.4% respectively for mammography.

In studies evaluating the presurgical assessment and staging of breast cancer, CEM showed a sensitivity, specificity, PPV, NPV and precision of 93%, 98%, 90%, 98% and 97% respectively. The surgical plan was modified by CEM in 18.4% of cases.

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

5.2.1    General Information
In the body, iopromide behaves like other highly hydrophilic, biologically inert, renally excreted compounds (e.g. mannitol or inulin).

5.2.2    Absorption and distribution

Following intravenous administration, plasma iopromide concentration declines rapidly due to distribution into the extracellular space and subsequent elimination. The total volume of distribution at steady-state is about 16 L, corresponding approximately to the volume of the extracellular space.

Plasma protein binding is negligible (about 1%). There is no indication that iopromide crosses the intact blood-brain barrier. A small amount crossed the placenta in animal studies (≤ 0.3% of the dose was found in rabbit fetuses). Following intrathecal administration, peak iodine concentration of approximately 4.5% of the administered dose was observed in the total plasma volume after 3.8 hours.

Following administration in the bile and/or pancreatic ducts during endoscopic retrograde cholangiopancreatography (ERCP), iodinated contrast media are systemically absorbed and reach peak plasma concentrations between 1 and 4 hours after administration. Peak serum iodine concentration, following administration of a mean dose of about 7.3 g iodine, was about 40 times lower than peak serum concentrations after administration of the respective intravenous doses.

5.2.3   Biotransformation

Iopromide is not metabolised.

5.2.4   Elimination

The terminal elimination half-life of iopromide is approximately 2 hours, irrespective of the dose.
In the dose range tested, the mean total clearance of iopromide is 106 ± 12 mL/min, which is comparable to renal clearance of 102 ± 15 mL/min. Iopromide is therefore almost exclusively eliminated by the kidneys. Only about 2% of the administered dose is eliminated via the faecal route within 3 days.

Approximately 60% of the dose is excreted in the urine within 3 hours of intravenous administration.
On average, ≥ 93% of the dose was recovered within 12 hours. Elimination is essentially complete within 24 hours.

Following intrathecal administration for myelography of the lumbar spine, plasma elimination of iopromide takes longer, with a terminal half-life of 14.9 ± 17 hours. About 80% of iopromide is eliminated by the kidneys within 72 hours.

Following administration into the bile and/or the pancreatic ducts for ERCP, serum concentration of urinary iodine normalised within 7 days.

5.2.5   Linearity/non-linearity

The pharmacokinetic parameters of iopromide in humans are dose-dependent in some cases (e.g. Cmax, AUC) and dose-independent in others (e.g. Vss, t1/2).

5.2.6   Characteristics in special patient populations

5.2.6.1 Elderly population (aged 65 years or more)
Middle-aged patients (49-64 years) and elderly patients (65-70 years), without severely impaired renal function, had total plasma clearance of between 74 and 114 mL/min (middle-aged group: mean 102 mL/min) and between 72 and 110 mL/min (elderly group: mean 89 mL/min), which is only marginally lower than that in healthy young subjects (88 to 138 mL/min, mean 106 mL/min).
Individual elimination half-lives are between 1.9 and 2.9 hours and between 1.5 and 2.7 hours respectively. Terminal half-lives are comparable to the range of 1.4 to 2.1 h in healthy young volunteers. The minor differences can be explained by glomerular filtration rate, which naturally decreases as age increases.

5.2.6.2 Paediatric Population

The pharmacokinetics of iopromide have not been studied in the paediatric population (see section “Posology and method of administration”).

5.2.6.3 Patients with renal impairment

In patients with impaired renal function, the plasma half-life of iopromide is longer, depending on the reduced glomerular filtration rate.

Plasma clearance was reduced to 49.4 mL/min/1.73 m2 (CV = 53%) in patients with mild or moderate renal impairment (80 > CLCR > 30 mL/min/1.73 m2) and to 18.1 mL/min/1.73 m2 (CV = 30%) in patients with severe renal impairment not dependent on dialysis (CLCR = 30-10 mL/min/1.73 m2).

Mean terminal half-life is 6.1 hours (CV = 43%) in patients with mild to moderate renal impairment (80 ≥ CLCR > 30 mL/min/1.73 m2) and 11.6 hours (CV = 49%) in patients with severe impairment not dependent on dialysis (CLCR = 30-10 mL/min/1.73 m2).

The amount recovered in urine within 6 hours of administration was 38% in patients with mild to moderate renal impairment and 26% in patients with severe impairment, compared with more than 83% in healthy volunteers. Recovery within 24 hours of administration was 60% in patients with mild to moderate renal impairment and 51% in patients with severe renal impairment, versus more than 95% in healthy volunteers.

Iopromide can be eliminated by haemodialysis. Approximately 60% of the iopromide dose is eliminated after 3 hours of dialysis.

5.2.6.4 Patients with hepatic impairment

Elimination is not affected by hepatic impairment because iopromide is not metabolised and only about 2% of the dose is excreted in the faeces.